Abstract: :
Purpose: Mustard agents are highly toxic and abundant warfarechemicals, primarily affecting ocular tissues, with no specifictreatment antidote. The purpose of the present study was toexamine the efficacy of novel metallo-complexes, known to inhibitthe formation of highly reactive free radicals, in reducingocular injury induced by nitrogen mustard (NM).Methods: Oneeye in each of 72 rabbits was exposed to 1-2% NM. Topical treatmentwith eye drops of a metallo-complex – either Zinc- orGallium-Desferrioxamine (Zn/DFO and Ga/DFO) - was compared totreatment with saline, zinc (chloride) or DFO alone. Examinersmasked to the treatment groups assessed the extent of ocularinjury and the response to treatment using clinical, histologicaland biochemical criteria.Results: Exposure to NM caused severeand long-lasting injury to ocular anterior segment structures.Topical application of Zn/DFO or Ga/DFO markedly reduced conjunctival,corneal, iris, and anterior chamber injury. In the cornea, fasterhealing of epithelial erosions occurred: at 3 days post-injury,average erosion size was 11.2 ± 3.9 and 28.3 ±3.2 mm2 for Zn/DFO and saline-treated eyes, respectively. Long-termcorneal opacification was reduced by more than 50% (p<0.05)in Zn/DFO treated eyes as compared to controls, and was associatedwith lower levels of neovascularization. In the anterior chamber,decreased inflammation and better maintenance of IOP was achieved:average IOP at 4 days post-injury was 19.3 ± 2.0, 27.4± 1.9 and 38.0 ± 2.4 mmHg for control non-exposedeyes, exposed and Zn/DFO-treated and exposed and saline-treatedeyes, respectively. Iris pigmentation and atrophy were reducedby more than 60% (p<0.05), less posterior synechiae formed,and cataractous changes were also markedly milder. Zinc chlorideor DFO alone provided lower levels of protection. Systemic anti-oxidantstatus was preserved in Zn/DFO and Ga/DFO treated animals ascompared with saline-treated. No toxic effects of the complexeswere observed.Conclusions: We hypothesize that Zn/DFO andGa/DFO act via combined "Push and-Pull" mechanisms that interferewith transition metal-dependent formation of free radicals,thus reducing mustard ocular injury. Topical use of these complexesshould be considered following exposure to Mustard gas, whichposes a threat in future terror attacks or on the battlefield.Further evaluation of the safety and efficacy in humans is required.